Approximately 1.7 million Americans over the age of 65 suffer from age-related macular degeneration (AMD). As the nation's population continues to age, this number is expected to grow by an estimated 200,000 new cases per year. Severe vision loss from AMD and other diseases affecting the posterior segment, including diabetic retinopathy, glaucoma, and retinitis pigmentosa accounts for most cases of irreversible blindness worldwide.
Currently, the treatment of posterior segment diseases is to a significant extent limited by the difficulty in delivering effective doses of drugs to target tissues in the posterior eye while avoiding toxicity. Four modes of administration are commonly used to deliver drugs to the posterior segment of the eye: topical, systemic, intraocular, and periocular administration.
Topical administration, for example the application of solutions to the surface of the eye, is the most common mode of administration of therapeutics for the pharmacologic management of ocular disease. Topical administration has the advantage of being minimally invasive; however, many factors can limit its usefulness. Examples include the significant barrier to solute flux provided by the corneal epithelium, and the rapid and extensive precorneal loss that occurs as the result of drainage and tear fluid turnover. It has been estimated that typically less than 5% of a topically applied drug permeates the cornea and reaches intraocular tissues. The major portion of the instilled dose is absorbed systemically by way of the conjunctiva, through the highly vascular conjunctival stroma and through the lid margin vessels. Significant systemic absorption also occurs when the solution enters the nasolacrimal duct and is absorbed by the nasal and nasopharyngeal mucosa. Despite the relatively small proportion of a topically applied drug dose that ultimately reaches anterior segment ocular tissues, topical formulations can be effective in some circumstances, largely because of the very high concentrations of drugs that can be administered.
Recent advances in topical drug delivery have focused on improving ocular drug contact time and drug delivery from the surface of the eye to the posterior segment. For example, ointments, gels, liposome formulations, and various sustained and controlled-release substrates, such as the Ocusert® system, collagen shields, and hydrogel lenses, have been developed to improve ocular drug contact time. Topical delivery systems using polymeric gels, colloidal systems, and cyclodextrins have also been investigated in an effort to improve drug delivery to the posterior segment. In spite of these efforts, the delivery of therapeutic doses of drugs to the posterior segment of the eye by topical routes remains a significant challenge.
Drugs for the treatment of posterior segment diseases can also be administered systemically. Although systemic administration can deliver drugs to the posterior eye, large systemic doses are typically required to yield therapeutic drug levels in the posterior vitreous, retina, or choroid. As a result, systemic administration is generally plagued by significant side effects associated with the administration of large systemic doses of the therapeutic agent.
Periocular drug delivery using subconjunctival or retrobulbal injections or placement of sustained-release devices provides another route for delivering drugs to the posterior tissues of the eye. This approach offers the potential for localized, sustained-release drug delivery. The average 17 cm2 surface area of the human sclera accounts for 95% of the total surface area of the globe and provides a significantly larger avenue for drug diffusion to the inside of the eye than the 1-cm2 surface area of the cornea. Also, regional differences in scleral thickness could be used to further optimize transscleral drug diffusion if sustained-release delivery devices or systems could be placed in regions where scleral permeability was greatest. The sclera, for example, is 1.0 mm thick near the optic nerve and an average of 0.53 mm thick at the corneoscleral limbus and thins to an average of 0.39 mm at the equator, where it can be as thin as 0.1 mm in a significant number of eyes. See Geroski, et al. Invest. Ophthalmol. Vis. Sci. 41(5):961-964 (2000).
Intravitreal injection represents the most common method for administering therapeutic drug levels to the posterior segment of the eye. While intravitreal injection offers the opportunity to control initial drug levels in the posterior segment of the eye while minimizing any systemic toxicity associated with the drug, intravitreal administration suffers some significant drawbacks. Intravitreal injections have several inherent potential side effects, including a risk of retinal detachment, hemorrhage, endophthalmitis, and cataract development. Repeat injections are frequently required, and they are not always well tolerated by the patient. Further, drugs injected directly into the vitreous are rapidly eliminated, making it difficult to maintain therapeutically effective levels of the drug in the posterior segment.
For drugs that are administered to regions of the body where they are rapidly eliminated (e.g., the posterior segment of the eye), are used to treat chronic diseases or disorders, and/or have a narrow therapeutically effective concentration range (i.e., therapeutic window), conventional drug delivery methods are inappropriate. Conventional drug administration involves periodic dosing of a therapeutic agent in a dosage formulation that ensures drug stability, activity, and bioavailability. Administration of the therapeutic agent typically results in a sharp initial increase in drug concentration (often to toxic levels), followed by a steady decline in concentration as the drug is cleared and/or metabolized. To maintain an effective concentration of the therapeutic agent in the posterior segment for the treatment of chronic eye diseases, repeated administration of the dosage formulation is typically required. The periodic drug delivery generates a drug concentration profile that oscillates over time, often spiking to toxic levels and/or dipping below the therapeutic window.
Controlled release formulations offer the potential to improve patient outcomes in these instances. Controlled release formulations provide the ability to minimize/eliminate spikes in drug concentration, minimizing side effects and/or toxicity. Controlled release formulations can also maintain the drug concentration within the therapeutic window for longer periods of time. As a result, these formulations are more comfortable and convenient for the patient, due to a diminished frequency of ocular injections.
Towards this end, intravitreal sustained-release devices have been investigated. The best known of these devices is the VITRASERT™ ganciclovir implant, used in the treatment of cytomegalovirus retinitis. However, implants such as VITRASERT™ require complex and undesirable intraocular surgery, and must be replaced periodically.
Sustained release formulations containing drugs encapsulated in biodegradable polymer particles are an attractive alternative. Nanoparticle and microparticle formulations can be injected as a suspension, obviating the need for intraocular implantation surgeries. As the polymer particles degrade and/or as the drug diffuses out of the polymer particles, the drug is released.
Several drawbacks have hampered the successful development of controlled release polymeric nanoparticle and microparticle formulations. First, it is often difficult to achieve high and/or controlled drug loading during particle formation, particularly for hydrophilic molecules such as doxorubicin. Grovender T. et al. J. Controlled Release 57(2):171-185 (1999). Second, it is difficult to achieve high drug encapsulation efficiency when forming polymeric particle, particularly polymeric nanoparticles. Most polymeric particles possess poorly encapsulated drug molecules on or near the particle surface. As a result, many particles display an undesirable biphasic drug release pattern. Upon injection, poorly encapsulated drug molecules on or near the surface of nanoparticles can quickly diffuse into solution, resulting in an initial burst release of drug. In the case of many polymeric nanoparticles, as high as 40-80% of the encapsulated drug molecules are released in a burst during the first several or tens of hours following administration. After the first 24 to 48 hours, drug release becomes significantly slower due to the increased diffusion barrier for drug molecules buried more deeply in polymer particles. Such particles can still produce a sharp initial increase in drug concentration upon administration, often to toxic levels.
Therefore, it is an object of the invention to provide polymer-drug conjugates with improved properties for the controlled delivery of active agents.
It is also an object of the invention to provide drug formulations capable of effectively delivering therapeutic levels of one or more active agents to the eye for an extended period of time.
It is a further object of the invention to provide improved methods of treating or preventing diseases or disorders of the eye.